Utility of Circulating Tumor DNA Assessment in Characterizing Recurrence Sites after Optimal Resection for Metastatic Colorectal Cancer.

BACKGROUND: Plasma circulating tumor DNA (ctDNA) is a promising biomarker for metastatic colorectal cancer (mCRC); however, its role in characterizing recurrence sites after mCRC resection remains poorly understood. This single-institution study investigated the timing of ctDNA detection and its levels in the context of recurrence at different sites after mCRC resection. STUDY DESIGN: Patients who underwent optimal resection of CRC metastases involving the peritoneum, distant lymph nodes, or liver, with serial postoperative tumor-informed ctDNA assessments (Signatera) were included. Recurrence sites, as defined by surveillance imaging or laparoscopy, were categorized as peritoneal-only and other distant sites (liver, lung, lymph nodes, or body wall). RESULTS: Among the 31 included patients, ctDNA was detected in all 26 (83.4%) patients with postoperative recurrence and was persistently undetectable in 5 patients who did not experience recurrence. At 3 months postsurgery, ctDNA was detected in 2 (25%) of 8 patients with peritoneal-only recurrence and 17 (94.4%) of 18 patients with distant recurrence (p < 0.001). Beyond 3 months, ctDNA was detected in the remaining 6 patients with peritoneal-only disease and 1 patient with distant disease. ctDNA detection preceded the clinical diagnosis of recurrence by a median of 9 weeks in both groups. At recurrence, peritoneal-only recurrent cases exhibited lower ctDNA levels (median 0.4 mean tumor molecules/mL, interquartile range 0.1 to 0.8) compared with distant recurrence (median 5.5 mean tumor molecules/mL, interquartile range 0.8 to 33.3, p = 0.004). CONCLUSIONS: Peritoneal-only recurrence was associated with delayed ctDNA detection and low levels of ctDNA after optimal resection for mCRC. ctDNA testing may effectively characterize recurrence sites and may help guide subsequent treatments specific to the disease sites involved.

Distance Traveled and Disparities in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The impact of distance traveled on cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) outcomes needs further investigation. METHODS: This retrospective study reviewed a prospectively managed single-center CRS/HIPEC 1992-2022 database. Zip codes were used to calculate distance traveled and to obtain data on income and education via census data. Patients were separated into three groups based on distance traveled in miles (local: ≤50 miles, regional: 51-99 miles, distant: ≥100 miles). Descriptive statistics, Kaplan-Meier method, and Cox regression were performed. RESULTS: The 1614 patients in the study traveled a median distance of 109.5 miles (interquartile range [IQR], 53.36-202.29 miles), with 23% traveling locally, 23.9% traveling regionally, and 53% traveling distantly. Those traveling distantly or regionally tended to be more white (distant: 87.8%, regional: 87.2%, local: 83.2%), affluent (distant: $61,944, regional: $65,014, local: $54,390), educated (% without high school diploma: distant: 10.6%, regional: 11.5%, local: 13.0%), less often uninsured (distant: 2.3%, regional: 4.6%, local: 5.2%) or with Medicaid (distant: 3.3%, regional: 1.3%, local: 9.7%). They more often had higher Peritoneal Carcinomatosis Index (PCI) scores (distant: 15.4, regional: 15.8, local: 12.7) and R2 resections (distant: 50.3%, regional: 52.2%, local: 40.5%). Median survival did not differ between the groups, and distance traveled was not a predictor of survival. CONCLUSION: More than 50% of the patients traveled farther than 100 miles for treatment. Although regionalization of CRS/HIPEC may be appropriate given the lack of survival difference based on distance traveled, those who traveled further had fewer health care disparities but higher PCI scores and more R2 resections, which raises concerns about access to care for the underserved, time to treatment, and surgical quality.

Cost Analysis and Financial Implications of a Peritoneal Surface Malignancy Program in the USA.

BACKGROUND: We aimed to describe the financial implications of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in the USA. MATERIALS AND METHODS: We conducted a retrospective cost analysis of 100 CRS/HIPEC procedures to examine the impact of patient and procedural factors on hospital costs and reimbursement. A comparison of surgeons' work relative value units (wRVUs) between CRS/HIPEC and a representative sample of complex surgical oncology procedures was made to assess the physicians' compensation rate. Univariable and multivariable backward logistic regression was used to analyze the association between perioperative variables and high direct cost (HDCs). RESULTS: The median direct cost per CRS/HIPEC procedure was US $44,770. The median hospital reimbursement was US $43,066, while professional reimbursement was US $8608, resulting in a positive contribution margin of US $7493/procedure. However, the contribution margin significantly varied with the payer mix. Privately insured patients had a positive median contribution margin of US $23,033, whereas Medicare-insured patients had a negative contribution margin of US $13,034. Length of stay (LOS) had the most significant association with HDC, and major complications had the most significant association with LOS. Finally, CRS/HIPEC procedures generated a median of 13 wRVU/h, which is significantly lower than the wRVU/h generated by open pancreatoduodenectomies, open gastrectomies, and hepatectomies. However, higher operation complexity and multiple visceral resections help compensate for the relatively low wRVU/h. CONCLUSIONS: CRS/HIPEC is an expensive operation, and prolonged LOS has the most significant impact on the total cost of the procedure. High-quality care is essential to improve patient outcomes and maintain the economic sustainability of the procedure.

Optimizing disease progression assessment using blinded central independent review and comparing it with investigator assessment in the PRIMA/ENGOT-ov26/GOG-3012 trial: challenges and solutions.

OBJECTIVE: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy. METHODS: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention. RESULTS: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups. CONCLUSION: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.

The Role of Additional Staining in the Assessment of the Peritoneal Regression Grading Score (PRGS) in Peritoneal Metastasis of Gastric Origin.

INTRODUCTION: The Peritoneal Regression Grading Score (PRGS) is a 4-tied histologic regression grading score for determining the response of peritoneal metastasis to chemotherapy. Peritoneal biopsies in every abdominal quadrant are recommended. A positive therapy response is defined as a decreasing or stable mean PRGS between 2 therapy cycles. The added value of periodic acid satin (PAS) and Ber-EP4 staining over HE staining for diagnosing PRGS1 (the absence of vital tumor cells) is unclear. MATERIALS AND METHODS: A total of 339 biopsies obtained during 76 laparoscopies in 33 patients with peritoneal metastasis of gastric cancer were analyzed. Biopsies classified as PRGS 1 (no residual tumor, n=95) or indefinite (n=50) were stained with PAS, and remaining indefinite or PRGS1 cases additionally stained with BerEP4. RESULTS: After PAS-staining tumor cells were detected in 28 out of 145 biopsies (19%), the remaining 117 biopsies were immunostained with Ber-EP4. Tumor cells were detected in 22 biopsies (19%). In total, additional staining allowed the detection of residual tumor cells in 50 out of 339 biopsies (15%) and changed the therapy response assessment in 7 out of 33 (21%) patients. CONCLUSIONS: In summary, 25% (24 out of 95) of initially tumor-free samples (PRGS1) showed residual tumor cells after additional staining with PAS and/or BerEp4. Immunohistochemistry provided important additional information (the presence of tumor cells) in 22 of all 339 biopsies (11.2%). Further staining reduced the instances of unclear diagnosis from 50 to 0 and changed the therapy response assessment in 7 out of 33 patients (21%). We recommend additional staining in PRGS1 or unclear cases.

Predictive performance of radiomics for peritoneal metastasis in patients with gastric cancer: a meta-analysis and radiomics quality assessment.

PURPOSE: The purpose of this meta-analysis is to systematically review the diagnostic performance of radiomic techniques in predicting peritoneal metastasis in patients with gastric cancer, and to evaluate the quality of current research. METHODS: We searched PubMed, Web of Science, EBSCO, Embase, and Cochrane databases for relevant studies up to April 3, 2023. Data extraction and quality evaluation were performed by two independent reviewers. Then we performed statistical analysis, including plotting the forest plot and summary receiver operating characteristic (SROC) curve, and source of heterogeneity analysis, through the MIDAS module in Stata 15. We performed meta-regression and subgroup analyses to analyze the sources of heterogeneity. Using the QUADAS-2 scale and the RQS scale to assess the quality of retrieved studies. RESULTS: Ten studies with 6199 patients were finally included in our meta-analysis. Pooled sensitivity and specificity were 0.77 (95% confidence interval [CI]: 0.66, 0.86), and 0.88 (95% CI 0.80, 0.93), respectively. The overall AUC was 0.89 (95% CI 0.86, 0.92). The heterogeneity of this meta-analysis was high, with I2 = 88% (95% CI 75,100). The result of meta-regression showed that QUADAS-2 results, RQS results and machine learning method led to heterogeneity in sensitivity and specificity (P < 0.05). Furthermore, the image segmentation area and the presence or absence of combined clinical factors were associated with sensitivity heterogeneity and specificity heterogeneity, respectively. CONCLUSION: Undoubtedly, radiomics has potential value in diagnosing peritoneal metastasis of gastric cancer, but the quality of current research is inconsistent, and more standardized and high-quality research is still needed in the future to achieve the transformation of radiomics results into clinical applications.

A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms.

BACKGROUND: There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma. METHODS: Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes. RESULTS: Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate. CONCLUSIONS: Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.

Hospitalization cost of Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC).

INTRODUCTION: Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of unresectable peritoneal carcinomatosis. Very little data is available on the costs of this treatment in France as there is currently no code for PIPAC in the French Common Classification of Medical Acts (CCAM). Our objective was to estimate the mean cost of hospitalization for PIPAC in two French public teaching hospitals. METHODS: The mean cost of hospitalization was estimated from the mean fixed-rate remuneration paid to the hospital and the mean additional costs of treatment paid by the hospital. At discharge a patient's hospitalization is classified into a diagnosis related group, which determines the fixed-rate remuneration paid to the hospital (obtained from the national hospitals database - PMSI). Costs of medical devices and drug treatments specific to PIPAC, not covered by the fixed-rate remuneration, were obtained from the hospital pharmacies. RESULTS: Between July 2016 and November 2021, 205 PIPAC procedures were performed on 79 patients (mean procedures per patient = 2.6). Mean operating room occupancy was 165 min. The mean fixed-rate remuneration received by the hospitals per PIPAC hospitalization was €4031. The actual mean cost per hospitalization was €6562 for a mean length-of-stay of 3.3 days. Thus, each PIPAC hospitalization cost the hospital €2531 on average. CONCLUSION: The current reimbursement of PIPAC treatment by the national health system is insufficient and represents only 61% of the real cost. The creation of a new fixed-rate remuneration for PIPAC taking into account this cost differential is necessary.

Impact of cumulative complications on 1-year treatment-related healthcare costs in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of all minor and major complications on treatment-related healthcare costs in patients who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of colorectal peritoneal metastases (PMs). METHOD: Patients with histologically proven colorectal PMs who underwent CRS + HIPEC from March 2006 to October 2019 in a tertiary referral centre were retrospectively identified from a prospectively maintained database. Patients were divided into six subgroups according to the severity of the complications, which were scored using the comprehensive complication index (CCI) (CCI 0-9.9, CCI 10-19.9, CCI 20-29.9, CCI 30-39.9, CCI 40-49.9, and CCI 50 or higher). Treatment-related healthcare costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the chi-squared test and Kruskal-Wallis H test. RESULTS: A total of 142 patients were included (CCI 0-9.9, 53 patients; CCI 10-19.9, 0 patients; CCI 20-29.9, 45 patients; CCI 30-39.9, 14 patients; CCI 40-49, 9 patients; and CCI 50 or higher, 21 patients). Median (interquartile range) treatment-related healthcare costs increased significantly and exponentially for the CCI 30-39, CCI 40-49, and CCI 50 or higher groups (€48 993 (€44 262-€84 805); €57 167 (€43 047-€67 591); and €82 219 (€55 487-€145 314) respectively) compared with those for the CCI 0-9.9 and CCI 20-29.9 groups (€33 856 (€24 433-€40 779) and €40 621 (€31 501-€58 761) respectively, P < 0.010). CONCLUSION: Treatment-related healthcare costs increase exponentially as more complications develop among patients who undergo CRS + HIPEC for the treatment of colorectal PMs. Anastomotic leakages after CRS + HIPEC lead to an increase of 295 per cent of treatment-related healthcare costs.

ASO Author Reflections: An Opportunity to Provide Cost-Conscious Care for Patients Undergoing CRS-HIPEC.

The substantial cost of care for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy can be augmented by changes in practice patterns. This report discusses the recent publication of the authors' group and their thoughts on cost-conscious cancer care.

Transformation of indwelling peritoneal catheter placement for malignant ascites from an inpatient to a day-case service: analysis of patient risk and financial implication.

AIM: To investigate the impact on patient outcomes, costs, and resources/infrastructure of inserting indwelling peritoneal catheters (IPC) during a day-case instead of an inpatient service. MATERIALS AND METHODS: A single-centre, retrospective analysis of patients receiving IPCs over a 4-year period was performed. Patients undergoing a day-case procedure were admitted in the morning for pre-procedural investigations, a 15.5 F PleurX IPC (BD, Wokingham, UK) was inserted, all accessible fluid drained and patients discharged the same day, barring any complications. Using electronic patient records, outcomes and complications (immediate/post-procedural) were recorded. Expenses and re-imbursement tariffs were obtained from the income department. RESULTS: Of 138 IPC procedures, 45.6% were undertaken after formal inpatient admission, 54.3% were undertaken as a day-case. The mean hospital stay was 2.51 bed-days for inpatient procedures (n=63) and 0.31 bed-days for day-case procedures (n=75; p<0.001). Day-case procedures saved 165 bed-days per year. Complication rates were 15.9% and 16% for inpatient and day-case procedures respectively (p=0.98). There was an estimated savings of £1,850.46 per day-case procedure or £138,784.50 annually. CONCLUSION: The placement of IPCs can safely be performed as a day-case procedure. There were substantial economic benefits as well as improved patient satisfaction, with no compromise in patient outcomes. Day-case IPC insertion is now standard practice at The Christie NHS Trust.

Assessment of postoperative pain after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of peritoneal metastasis.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, for the treatment of initially unresectable peritoneal metastasis (PM). Our objective was to assess postoperative pain and morbidity. METHODS: Between July 2016 and September 2020, data from 100 consecutive PIPAC procedures with oxaliplatin (PIPAC Ox) or doxorubicin-cisplatin (PIPAC C/D) in 49 patients with PM (all etiologies) were analyzed. Pain was self-assessed using a visual analog scale (VAS) of 0-10. RESULTS: The median PIPAC procedures per patient were 2 [1-3]. Patients indicated greatest pain at 4 pm on the day of the procedure (D0) and on postoperative D1 at 8 am and 4 pm. Postprocedural moderate-to-severe pain (VAS 4-10) was more frequent with PIPAC Ox than with PIPAC C/D, respectively 14 (36.8%) vs 7 (13.5%); p = 0.010. Hospitalization was longer for patients with moderate-to-severe pain than for others (median 4 days [3-7] vs 3 days [2-4], p = 0.004). Multivariate analysis identified oxaliplatin as a factor associated with greater pain (OR [95% CI], 2.95 [1.10-7.89]. Opiate administration was similar after PIPAC Ox and PIPAC C/D procedures, p = 0.477. CONCLUSION: PIPAC was well-tolerated, and pain was well-controlled in the majority of patients. Pain was greatest at 4 pm on D0 and 8 am and 4 pm on D1. PIPAC Ox is associated with greater pain than PIPAC C/D, independently of opiate treatment. Moderate-to-severe pain was associated with longer hospital stays.

Radiological assessment of peritoneal carcinomatosis: a primer for resident.

The imaging has critical responsibility in the assessment of peritoneal lesions along with estimating the overall extent. Valuing disease burden is crucial for selection of combining cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy (HIPEC) treatment. An approach that combines the strength of several imaging tools and increases diagnostic accuracy, should be chosen, even if the preferred imaging tool in patients with suspected Peritoneal Carcinomatosis (PC) is CT. The outcomes of PC are mainly correlated to tumor spread, localization, and lesion size. Accurate assessment of these features is critical for prognosis and treatment planning. These data can be evaluated by Peritoneal Cancer Index (PCI), a quantitative index suggested by Harman and Sugarbaker. Additionally, precise predictive biomarkers should be established to predict PC in patients at risk. The radiomics analysis could predict PC throughout the evaluation of cancers heterogeneity.